Matching of organ donors with potential recipients at the major histocompatibility complex (MHC) has resulted in improved success of renal transplants. However, at least 20% of well-matched cadaver grafts and 5-10% of HL-A sibling grafts are rejected. Several reports have indicated that the Lewis blood group system, which is unrelated to MHC, plays a significant role in the outcome of organ transplantation. However, each report has certain flaws. This research proposal tests the hypothesis that Lewis substances are strong antigens which function as histocompatibility determinants in man and influence about 10% of cadaver and living related donar grafts. four types of experiments will be done. (1) Radioimmunoassay procedures for Lewis substance will be developed to determine more precisely the Lewis phenotype of potential recipients. This system will resolve the current probvlem of whether or not our high proportion of Lewis negative dialysis patients (22% caucasion, 46% black) are, in act, genetically Le (a-b-). (2) Immunological and biochemical techniques will be used to determine the presence of Lewis synthetic enzymes for and de novo synthesis of Lewis antigens by kidney cells in short-term culture. If kidney cells are shown to produce Lewis substance, this will provide a mechanism for continued immuno-stimulation by a Lewis-positive graft placed into a Lewis-negative recipient. (3) Studies of the association between correct Lewis typing and transplant outcome will lead to a firm conclusion about the need for Lewis compatibility between donor and recipient. (4) Hu moral and cellular immune responses in Lewis incompatible recipients will be studied. Information obtained in this defined system will aid our understanding of the mechanisms of graft acceptance or rejection.